Trial in progress: A randomized phase II study of pembrolizumab with or without defactinib, a focal adhesion kinase inhibitor, following chemotherapy as a neoadjuvant and adjuvant treatment for resectable pancreatic ductal adenocarcinoma (PDAC).
Authors: John Davelaar, Zachariah Brown, Sheila Linden, Christina Rodriguez, Omer Elmadbouh, Jonathan A. Pachter, Jun Gong, Andrew Eugene Hendifar, Simon Lo, Srinivas Gaddam, Nicholas Nissen, Richard A. Burkhart, Lei Zheng, Arsen Osipov
Journal: Journal of Clinical Oncology (2022)

TPS4192 Background: PDAC is an aggressive cancer. It remains refractory to checkpoint inhibition because of its significant desmoplastic and immunosuppressive tumor microenvironment (TME). Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, is involved in tumor progression in many cancers and appears to be a targetable master regulator of the TME in PDAC. FAK inhibition combined with anti-PD1 antibody has been shown to modulate pancreatic stellate cells and decrease immunosuppressive myeloid and T-reg cells, leading to increased CD8 infiltration and improved survival in PDAC mouse models. A recent single arm phase I study of defactinib, a FAK inhibitor, combined with pembrolizumab, an anti-PD1 antibody, and chemotherapy was shown to be safe, and two confirmed partial responses were observed in patients with microsatellite-stable disease. Furthermore, increased CD8 T cell infiltration was observed in metastatic biopsies. Given the promising preclinical data and efficacy signals, as well as safety of the phase I clinical trial, our current study aims to assess the translational and clinical effects of sequentially combined defactinib and pembrolizumab following neoadjuvant and adjuvant chemotherapy in patients with high-risk resectable PDAC. Methods: This study is a multi-center, two-arm, randomized, open label, phase II clinical trial of neoadjuvant and adjuvant immunotherapy with defactinib and pembrolizumab, following neoadjuvant standard of care (SOC) gemcitabine and nab-paclitaxel in subjects with high-risk resectable PDAC. The primary objectives aim to assess changes in CD8 T cell intratumoral infiltration utilizing multiplex IHC and the pathologic complete response rate with defactinib and pembrolizumab or pembrolizumab alone, following neoadjuvant chemotherapy. Secondary objectives include assessment of disease-free survival, overall survival, and safety. Translational exploratory objectives include evaluating stromal and immune signatures among treatment groups via multiplex IHC and RNA/DNA sequencing. 36 subjects will be randomly assigned to receive 400 mg defactinib PO BID and 200 mg pembrolizumab IV every 3 weeks (Arm A) or 200 mg pembrolizumab IV alone every 3 weeks (Arm B). After enrollment, subjects will undergo 2 cycles (̃2 months) of standard neoadjuvant therapy of gemcitabine and nab-paclitaxel, followed by 2 cycles (6 weeks) of investigational treatment (Arm A or B) before surgical resection. Following surgery, subjects will receive SOC adjuvant chemotherapy followed by investigational treatment (Arm A or B) for 8 cycles (̃24 weeks). Key inclusion criteria include: resectable PDAC, CA 19-9&gt;200, no prior systemic treatment for PDAC, and ECOG PS ≤1. As of February 2022, 14 patients have been enrolled. Clinical trial information: NCT03727880.